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  • Review Article
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Recent insights how combined inhibition of immuno/proteasome subunits enables therapeutic efficacy

Genes & Immunity volume 21, pages 273–287 (2020)Cite this article

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Abstract

The proteasome is a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells that controls numerous cellular processes through regulated protein degradation. Proteasome inhibitors have significantly improved the survival of multiple myeloma patients. However, clinically approved proteasome inhibitors have failed to show efficacy against solid tumors, neither alone nor in combination with other therapies. Targeting the immunoproteasome with selective inhibitors has been therapeutically effective in preclinical models for several autoimmune diseases and colon cancer. Moreover, immunoproteasome inhibitors prevented the chronic rejection of allogeneic organ transplants. In recent years, it has become apparent that inhibition of one single active center of the proteasome is insufficient to achieve therapeutic benefits. In this review we summarize the latest insights how targeting multiple catalytically active proteasome subunits can interfere with disease progression in autoimmunity, growth of solid tumors, and allograft rejection.

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Fig. 1: Chemical structures of proteasome inhibitors described in this review.
Fig. 2: Co-inhibition in solid tumors.
Fig. 3: Co-inhibition in autoimmunity.

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Acknowledgements

This work was supported by the German Research Foundation (DFG) grants Nr. BA 4199/2-1 to MB and GR 1517/2.4, GR 1517/10-2 and GR 1517/27-1 to MG as well as by the SFB969 project C01 and the Else Kröner-Fresenius-Stiftung grant Nr. 2017_A28 to MG.

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  1. Division of Immunology, Department of Biology, University of Konstanz, D-78457, Konstanz, Germany

    Michael Basler & Marcus Groettrup

  2. Biotechnology Institute Thurgau at the University of Konstanz (BITg), CH-8280, Kreuzlingen, Switzerland

    Michael Basler & Marcus Groettrup

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  1. Michael Basler
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MB wrote the paper and designed the figures. MB and MG refined the paper.

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Correspondence to Michael Basler.

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Work in our laboratory described in this review was supported by the pharmaceutical companies Kezar Life Sciences, Principia Biopharma, and Takeda Pharmaceuticals.

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Basler, M., Groettrup, M. Recent insights how combined inhibition of immuno/proteasome subunits enables therapeutic efficacy. Genes Immun 21, 273–287 (2020). https://doi.org/10.1038/s41435-020-00109-1

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